? The sorting of G protein-coupled receptors (GPCRs) is a fundamental mechanism that controls the regulation of receptors associated with serious neuropsychiatric disorders, including schizophrenia and depression. Our laboratory has recently shown that the cellular fate of receptors can be controlled by specific protein interaction of the C-termini of some GPCRs with GASP (GPCR-associated sorting protein) [Whistler, 2002 #1]. In particular, GPCRs that interact with GASP appear to be targeted to the degradative pathway and those receptors that do not interact with GASP recycle. Intriguingly, GASP binds to the C-termini of D2 receptors and not D1 receptors. Furthermore, in preliminary experiments we have shown that the D2 receptor is targeted for degradation unlike the recycling D1 receptor. D2 receptor antagonists are one of the primary therapeutic treatments for schizophrenia, implicating aberrant dopamine signaling in this disease. We hypothesize that the dopamine signaling pathway may be altered in the disease state as a consequence of the D2 receptor being targeted to the degradative pathway. We have designed and made dominant negative proteins that are able to inhibit GASP function both in vitro and in vivo and have developed an experimentally favorable in vitro cell model system and in vivo techniques suitable for testing this hypothesis. These studies will determine whether GPCR sorting can be manipulated both in vitro and in vivo. This may provide a new spectrum of therapeutic targets for the treatment of schizophrenia and depression. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH068442-05
Application #
7234054
Study Section
Special Emphasis Panel (ZRG1-MDCN-1 (01))
Program Officer
Nadler, Laurie S
Project Start
2003-07-01
Project End
2009-04-30
Budget Start
2007-05-01
Budget End
2009-04-30
Support Year
5
Fiscal Year
2007
Total Cost
$276,832
Indirect Cost
Name
Ernest Gallo Clinic and Research Center
Department
Type
DUNS #
173995366
City
Emeryville
State
CA
Country
United States
Zip Code
94608
Thompson, Dawn; Whistler, Jennifer L (2011) Dopamine D(3) receptors are down-regulated following heterologous endocytosis by a specific interaction with G protein-coupled receptor-associated sorting protein-1. J Biol Chem 286:1598-608
Tschische, Pia; Moser, Elisabeth; Thompson, Dawn et al. (2010) The G-protein coupled receptor associated sorting protein GASP-1 regulates the signalling and trafficking of the viral chemokine receptor US28. Traffic 11:660-74
Thompson, Dawn; Martini, Lene; Whistler, Jennifer L (2010) Altered ratio of D1 and D2 dopamine receptors in mouse striatum is associated with behavioral sensitization to cocaine. PLoS One 5:e11038
Martini, Lene; Thompson, Dawn; Kharazia, Viktor et al. (2010) Differential regulation of behavioral tolerance to WIN55,212-2 by GASP1. Neuropsychopharmacology 35:1363-73
Thompson, Dawn; Pusch, Margareta; Whistler, Jennifer L (2007) Changes in G protein-coupled receptor sorting protein affinity regulate postendocytic targeting of G protein-coupled receptors. J Biol Chem 282:29178-85
Bartlett, Selena E; Enquist, Johan; Hopf, Frederic W et al. (2005) Dopamine responsiveness is regulated by targeted sorting of D2 receptors. Proc Natl Acad Sci U S A 102:11521-6